Exploiting patient-derived xenografts for the rational pre-clinical testing of interventions that result from drug and genetic screening
B-CELL MALIGNANCIES, TUMOR MICROENVIRONMENT, ONCOGENIC SIGNALING
B-cell malignancies often arise in settings of chronic infection or inflammation and autoimmunity. We have recently identified two novel cytokine/chemokine-driven pathways contributing critically to the pathogenesis of diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). These pathways are likely to be applicable also to other related mature B-cell malignancies and to converge on similar growth- promoting signaling modules. The goal of this proposal is to establish a joint research platform (a combined collection of cell lines, access to animal model platforms, unified drug screening platform, shared set of patient samples) that will bring together the specific expertise of a basic and a physician scientist with a shared focus on the tumor environment and its growth-promoting effects on malignant B-cells. The overall aim is to dissect the contribution of microenvironmental factors to the growth and dissemination of various lymphoma subtypes, identify novel druggable targets and to evaluate the efficacy of interventions that target cell-extrinsic pathways in suitable preclinical models.
Survey of ex vivo drug combination effects in chronic lymphocytic leukemia reveals synergistic drug effects and genetic dependencies
Lukas M, Velten B, Sellner L, Tomska K, Hüellein J, Walther T, Wagner L, Muley C, Wu B, Oleś M, Dietrich S, Jethwa A, Bohnenberger H, Lu J, Huber W, Zenz T. Survey of ex vivo drug combination effects in chronic lymphocytic leukemia reveals synergistic drug effects and genetic dependencies. Leukemia 34, 2934–2950 (2020). https://doi.org/10.1038/s41375-020-0846-5
Inhibitors of Bcl-2 and Bruton’s tyrosine kinase synergize to abrogate diffuse large B-cell lymphoma growth in vitro and in orthotopic xenotransplantation models
Bertram K, Leary PJ, Boudesco C, Fullin J, Stirm K, Dalal V, Zenz T, Tzankov A, Müller A. Leukemia. 2021 Nov 18